Methods and devices for crystallization by controlled evaporation

ABSTRACT

Methods and devices for controlled evaporation of solvent from a solution are provided. In one embodiment, a method for controlled evaporation of solvent from at least one solution includes filling a selected first set of wells in a multi-well plate with a first solution comprising at least one first solvent. The method also includes attaching an inlet manifold to the plate, the inlet manifold comprising an inlet port connected to and in fluid communication only with each of the wells in the selected first set of wells. The method further includes attaching an exhaust manifold to the plate, the exhaust manifold comprising an exhaust port connected to and in fluid communication only with each of the wells in the selected first set of wells. The method also includes introducing a gas into the inlet port and removing solvent vapor from the selected first set of wells.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.12/483,787, filed Jun. 12, 2009. The disclosure of the prior applicationis considered part of the disclosure of this application, and isincorporated by reference herein.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates generally to the crystallization of drugsubstances and, more particularly, relates to methods and devices forcrystallization by controlled evaporation.

2. Description of the Related Art

High quality crystals are used in a variety of studies throughout theprocess of developing a drug. In early development, solid forms of leadcompounds are available in fairly small quantities. These solid formsare studied to determine which forms are most suitable to move forwardin development. In late development, a well-characterized faun isselected for large scale manufacturing.

Crystals are typically grown by dissolving the drug substance in asuitable solvent, then evaporating the solvent. In a conventional,manual process for forming crystals, a scintillation vial is partiallyfilled with the drug and solvent solution and capped with aluminum foil.A small hole is poked in the foil. The vial then sits for some length oftime. The slow evaporation of the solvent through the small hole in thefoil favors crystal growth. There are many disadvantages, however, tothe conventional method. The lack of controls for making the hole, andtherefore the lack of consistency in hole size, leads to widely varyingrates of evaporation, even for the same drug substance and solvent.Experimental reproducibility is thus a serious challenge. Further, themethod cannot be scaled for use in small sample volumes, because theholes in the aluminum foil are no longer “small,” relatively speaking,when the sample volume is reduced to that of a well in a 96-well plate.In fact, in sample volumes below 0.5 mL, evaporation using holes pokedin aluminum foil is generally too fast to permit formation of highquality crystals. The problem of rapid evaporation is particularlysevere when the solvent is very volatile.

Current instruments that automate the process of crystal formation alsosuffer significant drawbacks. One device, for example, feeds inert gasclose to the surface of the wells in a 96-well plate using a manifoldwith a common, exhaust. This allows for controlled evaporation, however,only if the wells are filled with one solvent or multiple solvents ofsimilar volatilities. Thus, among other disadvantages, current designscannot accomplish controlled evaporation of multiple solvents ofdissimilar volatilities simultaneously. Thus, slow, controlledevaporation of multiple solvents of varying volatilities from smallvolume wells of, for example, a 96-well plate, remains a significantchallenge in the creation of high quality crystals.

SUMMARY OF THE INVENTION

In accordance with one aspect of the present invention, methods anddevices are provided for controlled evaporation of a solvent from asolution.

One embodiment is a device for controlled evaporation of solvent from atleast one solution. The device includes a plurality of wells configuredto hold the at least one solution; an inlet port for a first set of oneor more of the plurality of wells; an exhaust port for a second set ofone or more of the plurality of wells; and at least one flow controlorifice positioned between the inlet port and the exhaust port.

In another embodiment, a method for controlled evaporation of solventfrom at least one solution is provided. The method includes filling aselected first set of wells in a multi-well plate with a first solutionincluding at least one solvent. The method also includes attaching aninlet manifold to the plate, where the inlet manifold includes an inletport connected to and in fluid communication only with each of the wellsin the selected first set of wells. The method further includesattaching an exhaust manifold to the plate, where the exhaust manifoldincludes an exhaust port connected to and in fluid communication onlywith each of the wells in the selected first set of wells; introducing agas into the inlet port; and removing solvent vapor from the selectedfirst set of wells.

Yet another embodiment is a device for controlled evaporation of solventfrom at least one solution. The device includes a plate comprising aplurality of wells, where a selected first set of wells hold a firstsolution including at least one first solvent. The device also includesa first gas inlet connected to and in fluid communication only with theselected first set of wells; a first vapor removal outlet connected toand in fluid communication only with the selected first set of wells;and a means for controlling the rate at which solvent vapor flows fromthe first set of wells to the vapor removal outlet.

In still another embodiment, a device for controlled evaporation ofsolvent from at least one solution is provided. The device includes aplate comprising a first set of wells and a second set of wells, wherethe first set of wells hold a solution comprising at least one firstsolvent and the second set of wells hold a different solution comprisingat least one second solvent different from the at least one firstsolvent. The device also includes a set of gas inlets connected to andin fluid communication only with a corresponding set of wells; a set ofvapor removal outlets separately connected to and in fluid communicationwith the same corresponding set of wells; and means for separatelycontrolling vapor removal from the first and second sets of wells.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an exploded perspective view of an embodiment of a controlledevaporation device.

FIG. 2 is a cross-sectional view of one row of the device of FIG. 1.

FIG. 3 is a cross-sectional view of the leftmost well of the rowillustrated in FIG. 2.

FIG. 4 is a graph of vapor saturation levels in one well in anembodiment of a controlled evaporation device.

FIG. 5 is a graph of duty cycles for two solvents in an embodiment of acontrolled evaporation device.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

Any feature or combination of features described herein are includedwithin the scope of the present invention provided that the featuresincluded in any such combination are not mutually inconsistent as willbe apparent from the context, this description, and the knowledge of oneskilled in the art. In addition, any feature or combination of featuresmay be specifically excluded from any embodiment of the presentinvention. For purposes of summarizing the present invention, certainaspects, advantages and novel features of the present invention aredescribed herein. Of course, it is to be understood that not necessarilyall such aspects, advantages, or features will be embodied in anyparticular embodiment of the present invention.

In reference to the disclosure herein, for purposes of convenience andclarity only, directional terms, such as, top, bottom, left, right, up,down, upper, lower, over, above, below, beneath, rear, and front, may beused. Such directional terms should not be construed to limit the scopeof the invention in any manner. It is to be understood that embodimentspresented herein are by way of example and not by way of limitation. Theintent of the following detailed description, although discussingexemplary embodiments, is to be construed to cover all modifications,alternatives, and equivalents of the embodiments as may fall within thespirit and scope of the invention.

FIG. 1 is an exploded view of one embodiment of a device 100 forcontrolled evaporation of a solvent from a solution in accordance withthe invention. The device 100 includes a plate 105. In one embodiment,the plate 105 comprises ninety-six wells 110 arranged in rows andcolumns. The wells 110 are configured to hold solutions such as, forexample, a drug substance dissolved in solvent. The solvent may beconsist essentially of one substance such as water, DMSO, alcohol, orthe like, or may be a mixture of different substances. In some aspectsof the present invention, the solvent in the solution evaporates,leaving crystals of the drug substance in the wells 110. The solutionscontained in the plate 105 can be dissimilar, and can include drugsubstances dissolved in different solvents of varying volatilities.

The device 100 also includes an inlet manifold 115 that can bepositioned over and connected to the plate 105. The inlet manifold 115includes one or more inlet ports 120. The inlet ports are connected tochannels within the inlet manifold configured to allow for theintroduction of ambient air or a gas into the wells 110. The channelsare not shown in FIG. 1 but are shown in FIGS. 2 and 3. Seals 125, whichmay comprise o-rings, may be provided to create a seal between the inletmanifold 115 and the plate 105. The seals 125 may prevent gas and/orsolvent vapor from escaping between the inlet manifold 115 and the plate105.

The device 100 according to one embodiment includes an exhaust manifold130. The exhaust manifold 130 can include one or, more exhaust ports135, or vapor removal outlets, configured to allow for the removal ofgas and/or solvent vapor from the wells 110. The exhaust ports 135 areconnected to channels within the exhaust manifold which are not shown inFIG. 1 but are shown in FIGS. 2 and 3. The exhaust manifold 130 ispositioned over and connected to the inlet manifold 115. Seals 155, 157,which may comprise o-rings, spring energized seals, or the like, may beprovided to prevent gas and solvent vapor from escaping between theexhaust manifold 130 and the inlet manifold 115. The seals 155, 157 mayalso ensure gas and solvent vapor only leave the exhaust manifold 130through the exhaust port(s) 135. In addition, the inlet ports 120 andthe exhaust ports 135 may be coupled to fittings 122, 137, respectively.

The device 100 can also include an upper outlet tube 140, a flow controldisk 150, and a lower outlet tube 145 configured to allow for theremoval of gas and solvent vapor from the wells 110. Thus, in someaspects, the exhaust port 135 is opened to allow gas to flow from theinlet port 120; through the lower outlet tube 145, the disk 150, and theupper outlet 140; and finally to the exhaust port 135 and out of thedevice 100. As the gas flows out of the device, it can carry air withsolvent vapor to the exhaust port 135 and out of the device 100. Asexplained further below, the exhaust port 135 can be opened at specifictimes and for specific durations depending on the volatility of asolvent in the well 110. In one embodiment, the frequency and durationof the open periods is programmed so that solvent vapor leaves thedevice at a precisely controlled rate.

The disk 150 includes an orifice for flow control that allows gas andsolvent vapor to flow to the exhaust port 135 and out the device 100.According to one embodiment, the disk 150 is a sapphire disk. Theorifice in disk 150 may be precision-drilled with a diameter selected toproduce a desired rate at which gas and solvent vapor flow out of thewell when the exhaust port 135 is opened.

The elements of the embodiment of FIG. 1 will now be described in moredetail with reference to FIGS. 2 and 3. FIG. 2 is a cross-sectional viewof one row 160 of the device 100 illustrated in FIG. 1. In theembodiment illustrated in FIG. 2, twelve wells 110 are arranged in oneof eight rows 160 of the plate 105. Each of the twelve wells 110 canhold a solution 165 or, alternatively, a subset of the twelve wells 110can hold a solution 165. FIG. 3 is a cross-sectional view of theleftmost well of the row 160 illustrated in FIG. 2. According to oneembodiment, the well 110 is one of ninety-six wells in the plate 105.The plate 105 can be made of any suitable material, including plastic ora metal, such as aluminum. The plate 105 and/or the wells 110 mayinclude various types of coatings such as PTFE, other plastic materials,or metals such as gold so that they are inert to the solution(s) 165.

Referring now to FIGS. 2 and 3, the well 110 includes a head space 170between the solution 165 and the inlet manifold 115. In embodimentswhere the solution 165 comprises a drug substance dissolved in asolvent, a portion of the solvent in the solution 165 evaporates intothe space 170 above the solution 165. During evaporation, solventmolecules leave the surface of the solution 165 and are present in thespace 170 in gaseous or vapor form. More volatile solvents arecharacterized by higher evaporation rates and higher evaporated solventconcentrations in the head space 170.

As described above, the inlet manifold 115 includes an inlet port 120. Agas can be introduced into each well 110 in the row 160 through theinlet port 120. The intake manifold 115 according to some aspectsincludes a plurality of inlet channels 180, with each inlet channel 180connected to and in fluid communication with one row and the wellsassociated with that row. Thus, gas can be introduced into the inletport 120 and flow through the inlet channels 180 to the wells 110. Thelower outlet tube 145 extends through the inlet manifold 115 into headspace 170 above the solution 165. The disk 150 according to oneembodiment is positioned above and in fluid communication with the loweroutlet tube 145. The disk 150 includes an orifice 175. The orifice 175may be a precision-drilled orifice to provide gas flow rate control fromthe head space 170 to the exhaust manifold 130. The exhaust manifold 130comprises a plurality of exhaust channels 185, with each exhaust channel185 connected to and in fluid communication with one row and the wellsassociated with that row. The disk 150 and the lower outlet tube 145 arein fluid communication with the upper outlet tube 140 and the exhaustchannels 185 such that gas and solvent vapor can move from the space 170to the exhaust manifold 130 and exit the device 100 through the exhaustport 135. The exhaust port 135 can be open to ambient pressure orsubjected to a vacuum to draw the gas and solvent vapor out of thedevice 100.

The device 100 can also include an exhaust valve 180 configured to openand close the exhaust port 135. In some embodiments, the exhaust port135 is open to ambient pressure when the exhaust valve 180 is open,allowing gas and solvent vapor to flow from the space 170 above thesolution 165, through the lower outlet tube 145, the disk 150, the upperoutlet tube 140, and the exhaust port 135 to the atmosphere. When theexhaust valve 180 is closed, gas and solvent vapor do not exit to theatmosphere.

Persons of skill in the art will understand that the device 100 is notlimited to a specific number of rows or columns of wells, and that oneinlet port 120 and/or one exhaust port 135 may be connected to and influid communication with more than one row or with portions of a row.Similarly, it will be understood that the plate 105 is not limited to anarrangement of “rows” and “columns,” but can be arranged in any suitablemanner. Wells in the plate 105 may be arranged in quadrants, forexample, with one inlet port 120 and/or one exhaust port 135 connectedto and in fluid communication with one quadrant.

The device 100 can be assembled in various ways. In one embodiment, theexhaust manifold 130 is assembled first, is then coupled to the inletmanifold, and the combination is attached to the plate. To assemble theexhaust manifold 130, the upper outlet tubes 140 are placed in theexhaust manifold 130, followed by the seals 155. The disks 150 may bethreaded and screwed or press fit into countersunk holes provided in theexhaust manifold 130. The lower outlet tubes 145 are next placed in theexhaust manifold, held in place by additional seal 157. The exhaustmanifold 130 is then placed over the inlet manifold 115 such that thelower outlet tubes 145 extend through openings in the inlet manifold 115and into the head spaces 170 of the wells 110. The exhaust manifold 130can then be secured to the inlet manifold 115 with fasteners such asscrews or clamps. Next, the wells 110 of the plate 105 are filled withthe solution(s) 165. Finally, the assembled manifolds 115, 130 arepositioned over and connected to the plate 105 with fasteners such asscrews or clamps. The inlet manifold 115 can include integrated seals125 such that the seals 125 mate with the openings in the wells 110 whenthe inlet manifold 115 is connected to the plate 105. In anotherembodiment, the seals 125 are positioned over the openings in the wells110 before the inlet manifold 115 is connected to the plate 105. Personsof skill in the art will understand that the device 100 need not befully disassembled after each use. Thus, the assembled and coupledmanifolds 115, 130 can remain assembled and be fastened to differentplates 105 for each different evaporation sequence.

Solvent vapor can move from the space 170, through the lower outlet tube145, the orifice 175 in the disk 150, and the upper outlet tube 140 tothe exhaust port 135. If the exhaust port 135 is open to the ambientair, or if the exhaust valve 180, if provided, is open, the solventvapor leaves the exhaust port 135 and the device 100. If the exhaustport is left open, the rate of solvent evaporation is then controlled bythe size of the flow control orifice 175 and the inlet to outletpressure drop.

According to one embodiment, a gas is introduced into the space 170through the inlet port 120. The gas can be a dry, inert gas such as, butnot limited to, nitrogen. The gas introduced through the inlet port 120can be at ambient pressure. Alternatively, the gas can be introduced ata pressure greater than ambient pressure, such as, for example, 5 poundsper square inch (psi) over ambient pressure. When the exhaust port 135is closed, the gas flows from the inlet port 120 into the space 170 andsolvent vapor accumulates in the head space 170 and the lower outlettube 145.

Advantageously, the exhaust port 135 may be kept closed, thenperiodically opened to allow gas and solvent vapor to leave the space170 and the device 100 through the exhaust port 135. When the exhaustport is opened, the gas introduced into the well 110 flushes a portionof the solvent vapor out of the space 170, through the exhaust port 135,and out of the device 100. The exhaust ports 135 associated with eachrow 160 may be independently and selectively opened at certain times andfor certain periods of time based on the volatility of the solventscontained in each row.

During the time intervals when the exhaust port 135 is kept closed, theair in the space 170 can become saturated or nearly saturated withsolvent vapor. In one embodiment, for example, the air in the space 170reaches a high vapor concentration during the periods when the exhaustport 135 is closed. The air in the space 170 may approach 90 percent oreven approximately 100 percent saturation. The degree of vaporsaturation reached before the exhaust port 135 is opened can be selectedand optimized to allow for a constant or near constant rate ofevaporation of the solvent in the solution 165. For example, the maximumdesired vapor saturation may be selected based on the particularvolatility of the solution 165 in the well 110, and/or the similarvolatility of solutions in the eight wells 110 in one row 160.

When the exhaust port 135 is opened, the gas can flow from the inletport 120, to the space 170, then through the lower outlet tube 145,carrying a portion of the air with solvent vapor out of the space 170 asthe gas flows to the exhaust port 135. When the exhaust port is open,the rate of flow of the solvent vapor out of the device 100 isdetermined mainly by the size of orifice 175, although the inlet tooutlet pressure difference can have an effect on flow rate also.

The disk 150 can be made of any suitable material, including, but notlimited to, sapphire. For example, sapphire disks with orifices arecommercially available and suitable for use in embodiments of the device100. In one embodiment, an orifice with a diameter of approximately 34microns is drilled through a sapphire disk 150. As shown in FIG. 3, theprecision-drilled portion of the disk 150 need not extend the entirelength of the disk 150. It will be understood that the flow controlorifice is a controlled, narrow-diameter region that can be located inany suitable portion of the disk 150. The diameter of the orifice can beselected to increase or decrease the rate at which gas and solvent vaporflow out of the space 170 to the exhaust port 135 when the port isopened. Thus, control over the flow of solvent vapor out of the device100 is provided by selecting the pressure at the port(s) 120, 135,opening and closing the exhaust port 135 according to a selected dutycycle, and selecting the disk flow control orifice size.

It will be appreciated that the contribution of any one factorcontrolling flow of solvent vapor out of the device 100 can be more orless than the contribution of another factor controlling flow of vapor.Although it will be appreciated that these parameters may vary widely,in embodiments found to be especially advantageous, a disk flow controlorifice size will be less than about 100 microns, and the input tooutput pressure difference may be about 10-20 pounds per square inch(psi). This results in a low flow rate when the exhaust port is openthat is fairly insensitive to the presence of moderate changes orfluctuations in inlet to outlet pressure. This configuration is usefulbecause the pressure differential is the least accurately controllableaspect of the system compared to disk orifice size and duty cycletiming. Because the orifice and duty cycle can be controlled with highaccuracy, extremely accurate and repeatable control over solventevaporation is possible.

Referring now to FIG. 4, the exhaust port 135 may be opened and closedat a selected duty cycle, to allow air with solvent vapor to leave thespace 170 and the device 100. Thus, the evaporation of solvent from thesolution 165 can be controlled wholly or in part by opening the exhaustport 135 according to this selected duty cycle. In one embodiment, forexample, the duty cycle can be selected such that the air in the space170 approaches 100 percent vapor saturation before the exhaust port 135is opened. While the exhaust port is open, the orifice in the disk 150limits the outflow of gas and solvent vapor from the space 170, suchthat only a portion of air saturated with vapor leaves the space 170.Then, the duty cycle can be timed to end such that the air in the space170 is approximately 90 percent saturated with solvent vapor when theexhaust port 135 is closed.

The average saturation level of the air in the space 170 over the courseof the evaporation process may be held nearly constant, and deviationsfrom this average value are relatively small. The graph in FIG. 4illustrates the nearly constant nature of the average saturation levelaccording to one embodiment. In this example embodiment, the saturationlevel in the space 170 reaches approximately 95 percent before the startof each open time, then drops to approximately 80 percent at the end ofeach open time. After the exhaust port 135 is closed, the concentrationof solvent in the space 170 begins increasing again and the saturationlevel begins rising above the lower limit of 80 percent. As the vaporsaturation increases, the evaporation rate of the solvent slows butevaporation continues. The opening of the exhaust port 135 can be timedto begin before or just when evaporation of the solvent significantlyslows or stops. Controlling the saturation level of the air in the space170 such that it moves between two closely spaced saturation levelsproduces a constant or steady evaporation of solvent from the solutionin the well 110.

The evaporation of the solvent with the methods and devices describedherein is reproducible and efficient, as the solvent is not allowed toevaporate too quickly, preventing or hindering formation of high qualitycrystals, nor is the solvent allowed to evaporate too slowly, resultingin unnecessary delay in the evaporation process. In addition,embodiments of the present invention can be scaled to allow evaporationof a solvent from small volume wells such as, but not limited to, thewells in a 96-well plate, thus eliminating the drawbacks associated withholes in aluminum foil that can allow the solvent to evaporate tooquickly and prevent formation of high quality drug crystals.

Furthermore, embodiments of the present invention can allow for thecontrolled evaporation of multiple solvents of varying volatilities inone plate 105 by separately controlling the evaporation rate fordifferent sets of wells. As described above, in some embodiments eachinlet port 120 is connected to and in fluid communication with only onerow 160 and the wells 110 associated with that row, and each exhaustport 135 is connected to and in fluid communication with only one row160 and the wells 110 associated with that row. In this embodiment, eachrow 160 is connected to one inlet port and one exhaust port. A given rowmay hold solutions comprising solvents of the same or similarvolatility, but different from one or more other rows. The wells 110associated with a given row, holding solutions of the same or similarvolatility, receive the same gas at the same inlet-outlet pressure dropat the same exhaust duty cycle. A different row holding differentsolvents may receive the same or different gas at a different exhaustduty cycle. Different orifice sizes might also be provided for differentwells or sets of wells, although this can be inconvenient in thatdifferent manifolds would be used for different plates. This is alsogenerally unnecessary, as it has been found that duty cycle control isnormally sufficient for good performance. It would also be possible toprovide different pressure differentials, but as described above, thisis generally a less advantageous method of evaporation control.

Thus, referring again to FIG. 1, the twelve wells 110 of a first row 160may be filled with one solution comprising a very volatile solvent, andthe twelve wells 110 of a second row 190 may be filled with a secondsolution comprising a relatively stable solvent. In another embodiment,the twelve wells 110 of the first row 160 are not filled with identicalsolutions, but with solutions of similarly high volatilities, and thetwelve wells 110 of the second row 190 are filled with solutionscomprising different but relatively stable solvents. The inlet port 120and the exhaust port 135 associated with the first row 160, as well asthe disks 150 associated with each well in the first row 160, controlthe evaporation of solvents from the solutions only in the first row160. Similarly, the inlet port 120, the exhaust port 135, and the disks150 associated with the second row 190, control the evaporation ofsolvents from the solutions only in the second row 190. Thus,evaporation of solvents from the solutions in the second row 190 canoccur independently and unaffected by evaporation occurring in the firstrow 160. Thus, the pressure of the gas introduced into the wells, theduty cycle parameters, and the size of the orifice in the disks 150 canbe independently selected and optimized for each row in the plate 105based on the characteristics of the solvents in each row.

As noted above, embodiments of the present invention can also allow forthe controlled evaporation of multiple solvents of the same, similar, ordifferent volatilities from one well 110. For example, one well 110 canhold a solution comprising multiple, different solvents. Cosolvents arecommonly used in the crystallization process to take advantage of thedifferent volatilities and physical and/or chemical characteristics ofthe different solvents.

The device 100 may include an inlet pressure regulator that controls thepressure of the gas introduced into the inlet port 120 and a controllerthat controls the opening and closing of the exhaust valve 180, and thusthe duty cycle, of a row 160. The controller can individually andseparately control the opening and closing of the exhaust valves 180,and thus control the duty cycles, associated with multiple rows in theplate 105. In some aspects, the controller controls the opening andclosing of the exhaust valves 180 according to programmed duty cycles.The programmed duty cycles can be selected and optimized as describedabove to ensure constant and/or steady evaporation of the solvent fromthe solution 165. Thus, according to some aspects, evaporation of asolvent from a solution can be automated or semi-automated, and resultin consistent, reproducible results over multiple evaporation cycles.

FIG. 5 illustrates selection of different duty cycles to optimizeevaporation of two different solvents, Solvent 1 and Solvent 2. In theexample embodiment illustrated in FIG. 5, Solvent 1 is more volatilethan Solvent 2. Thus, after the exhaust ports 135 associated withSolvents 1 and 2 are closed following an open period, Solvent 1 beginsto evaporate more quickly than Solvent 2. As a result, the air in thespace 170 above Solvent 1 approaches saturation more quickly than theair over Solvent 2. To ensure the steady, slow evaporation of Solvent 1,the open period of cycle 210 for Solvent 1 is programmed to begin at atime A, before the open period of cycle 220 for Solvent 2 is programmedto begin. At a later time C, the air above Solvent 2 also approachessaturation. The open period of cycle 220 for Solvent 2 is thusprogrammed to begin at or around time C.

Because Solvent 1 is more volatile than Solvent 2, the vapor associatedwith Solvent 1 will have a higher concentration in the head space thanthe vapor associated with Solvent 2. Thus, opening the exhaust valvesassociated with Solvents 1 and 2 for the same amount of time would leadto more Solvent 1 vapor leaving the device compared to Solvent 2 vaporleaving the device. The evaporation rates of Solvents 1 and 2 can bematched or more closely aligned by programming the duration of the openperiod 230 for Solvent 1 to be less than the duration of the open period240 for Solvent 2. When the exhaust valve associated with the lessvolatile Solvent 2 is opened, a less concentrated vapor leaves thedevice during a longer open period, such that approximately equalamounts of Solvent 1 vapor and Solvent 2 vapor leave the device, therebyequalizing evaporation rates.

Thus, according to some embodiments, the controller can cycle theexhaust valves 180 associated with each row 160 such that theevaporation of solvents with very different volatilities progresses atthe same or a similar rate. As a result, solvents with dissimilarvolatilities can be evaporated from the wells in a single plate 105 overthe same or a very similar period of time, such that the variousevaporation processes occurring in the plate 105 are timed to begin andend at roughly the same time. This can allow drug crystals to becollected from all of the wells 110 in the plate 105 at one time,freeing all of the wells 110 of the plate 105 at one time to be refilledwith new solutions for evaporation.

Embodiments of the present invention also include controlling solventevaporation by regulating the temperature of the plate 105. Changing thetemperature of the plate 105 can change the evaporation rate of thesolvent in the wells 110, and thus the solvent vapor pressure in thehead space 170 between open periods. During evaporation, an externalsource can add heat to the endothermic evaporation process. The plate105 can be heated by an external source, for example, such that thesolutions 165 in the wells 110 are heated. In one embodiment, thetemperature of plate 105 is increased for more volatile solutions withhigher evaporation rates to maintain a constant solution temperature andsolvent evaporation rate. In another embodiment, the evaporation rate ofa solvent is increased or decreased by setting the plate temperatureabove or below room temperature.

The above-described embodiments have been provided by way of example,and the present invention is not limited to these examples. Multiplevariations and modifications to the disclosed embodiments will occur, tothe extent not mutually exclusive, to those skilled in the art uponconsideration of the foregoing description. Additionally, othercombinations, omissions, substitutions and modifications will beapparent to the skilled artisan in view of the disclosure herein.Accordingly, the present invention is not intended to be limited by thedisclosed embodiments.

1. A method for controlled evaporation of solvent from at least onesolution, comprising: filling a selected first set of wells in amulti-well plate with a first solution comprising at least one firstsolvent; attaching an inlet manifold to the plate, the inlet manifoldcomprising an inlet port connected to and in fluid communication onlywith each of the wells in the selected first set of wells; attaching anexhaust manifold to the plate, the exhaust manifold comprising anexhaust port connected to and in fluid communication only with each ofthe wells in the selected first set of wells; introducing a gas into theinlet port; and removing solvent vapor from the selected first set ofwells.
 2. The method of claim 1, further comprising: filling a selectedsecond set of wells in the plate with a second solution comprising atleast one second solvent, wherein the inlet manifold comprises an inletport connected to and in fluid communication only with each of the wellsin the selected second set of wells and wherein the exhaust manifoldcomprises an exhaust port connected to and in fluid communication onlywith each of the wells in the selected second set of wells; selectivelyremoving solvent vapor from the selected second set of wells.
 3. Themethod of claim 2, wherein the at least one first solvent and the atleast one second solvent are different.
 4. The method of claim 3,further comprising applying a vacuum to one or more exhaust ports. 5.The method of claim 4, further comprising regulating the pressure of thegas introduced into one or more inlet ports.
 6. The method of claim 1,wherein the gas is an inert gas.
 7. The method of claim 1, wherein thegas is nitrogen.
 8. The method of claim 2, further comprisingcontrolling the temperature of the first solution and the secondsolution.
 9. The method of claim 1, further comprising controlling therate at which solvent vapor from a head space above the first solutionin at least one well flows to the exhaust port.
 10. The method of claim1, further comprising regulating the pressure of the gas introduced intothe inlet port.
 11. The method of claim 1, further comprisingcontrolling opening and closing of the exhaust port according to aselected duty cycle.
 12. The method of claim 1, further comprisingheating the first solution.